BIOCHEMICAL STUDIES

生化研究

• 批准号: 3806171
• 负责人: ROBERT S SAWYER
• 金额: --
• 依托单位: ST. VINCENT CATHOLIC MEDICAL CTR NURSING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3806171
• 关键词: DNA directed RNA polymerase; DNA replication; N phosphonoacetyl L aspartate; adenine phosphoribosyltransferase; aminoacid metabolism; antimetabolites; antineoplastics; breast neoplasms; combination chemotherapy; creatine; cytidine; dihydrofolate reductase; disease /disorder model; dosage; drug metabolism; drug screening /evaluation; enzyme inhibitors; fluorouracil; glycolysis; high performance liquid chromatography; human tissue; interferons; laboratory mouse; methotrexate; neoplasm /cancer chemotherapy; nuclear magnetic resonance spectroscopy; nucleic acid inhibitor; pharmacokinetics; phosphotransferases; pyrimidine nucleotides; thymidylate synthase; uridine

The overall goal of this research program is to establish a rational foundation for the combination chemotherapy of cancer. The approach is based on the concept of employing combinations of metabolites and antimetabolites to modulate biochemical pathways with the view of achieving maximal cancer cell damage while simultaneously protecting moral host cells from drug toxicity. Much of the basic information upon which a rational for a particular drug combination is based comes from in vitro studies of others. However, since the ultimate utility of a drug combination depends upon the selective achievement of the appropriate modulation(s) of biochemical pathways in vivo, studies in Research Project 2 will be designed to determine the biochemical effect of a given modulating agent on the final activity of the primary effector agent in vivo. Thus, therapeutic results from a particular drug manipulation, obtained as expected on the basis of the biochemical information that prompted that manipulation, will be confirmed on a biochemical level to insure that the biological results are related to the predicted biochemical changes. Unexpected therapeutic results will be explored at the biochemical level to provide new information that will be utilized to alter the drug combination (or schedule) so as to achieve the desired therapeutic advance. (It must be stressed that the NMR and biochemical studies will be performed with tissues obtained from mice undergoing the in vivo therapeutic regimen in question). Of great importance, these in vivo biochemical, pharmacological, and NMR studies will provide guidelines for comparative pharmacological, and biochemical and NMR studies in the clinic (Research Project 3, Clinical Studies) which will be used to adjust promising therapeutic drug regimens for translation from the animal tumor model to cancer patients. The combined in vivo biological and biochemical findings, Project 1 and 2, lead to guidelines for specific clinical trials; feedback from Project 3, Clinical Studies, may suggest new experimental studies and refinements.

该研究计划的总体目标是建立一个理性的 癌症组合化疗的基础。 方法是 基于采用代谢物和组合的概念 抗超代谢物调节生化途径，以实现 最大的癌细胞损害同时保护道德宿主细胞 来自药物毒性。 合理的许多基本信息 特定的药物组合是基于的 其他的。 但是，由于药物组合的最终效用取决于 选择性实现适当的调制 体内生化途径，研究项目2中的研究将设计 确定给定调节剂对最终的生化效应 体内主要效应剂的活性。 因此，治疗结果 根据特定的药物操纵，根据预期 促使操纵的生化信息将是 在生化水平上确认，以确保生物学结果是 与预测的生化变化有关。 意外的治疗 结果将在生化层探索以提供新信息 这将用于更改药物组合（或时间表），以便 实现所需的治疗进展。 （必须强调的是NMR 并将使用从小鼠获得的组织进行生化研究 正在接受有关的体内治疗方案）。 非常重要的是，这些体内生化，药理学和NMR 研究将为比较药理和 诊所的生化和NMR研究（研究项目3，临床 研究）将用于调整有希望的治疗药物方案 用于从动物肿瘤模型转换为癌症患者。 这 体内生物学和生化发现，项目1和2，铅 针对特定临床试验的指南；项目3的反馈， 临床研究可能建议新的实验研究和改进。